Aminoalkoxybenzenesulfonamides



United States Patent ()fiice 3,127,446 Patented Mar. 31, 1964 3,127,446 AMIINUALKOXYBENZENESULFUNAMIDES William L. Holmes, Basement, Pa, assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporahion of Pennsylvania N Drawing. Filed June 12, 1962, Ser. No. 201,752 Claims. (Cl. 260-556) 5 R3\ /Rl N-S O X-alk-N R4 R2 e Formula 1 in which:

R and R are respectively lower alkyl of 18 carbons or, when taken together with the nitrogen atom to which they are attached, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl or N-lower alkylpiperazinyl;

R and R are respectively hydrogen, piperazinyl or as defined for R and R R and R are respectively the inert substituents common to the art such as hydrogen, lower alkyl such as methyl or ethyl, lower alkoxy such as methoxy or ethoxy, trifluoromethyl, or halo such as chloro, bromo or fluoro preferably substituted in both positions meta to the sulfonyl group;

X is sulfur or oxygen; or

Alk is a lower alkylene chain of from 26 carbon atoms inclusive separating X and the amine function by at least 2 carbon atoms.

Preferred and advantageous compounds are those in which R R are all methyl or ethyl, R and R are methyl, methoxy or chloro substituted in both positions ortho to the X substituent and alk is ethylene, isopropylene or propylene.

This invention also includes nontoxic, pharmaceutically acceptable addition compounds of the bases described above such as those formed with pharmacologically acceptable acids such as hydrochloric, hydrobromic, sulfuric, maleic, ethanedisulfonic, tannic, phosphoric, sulfamic, acetic, pamoic, mandelic, etc. or such as those formed with a medicinally acceptable active halo or sulfonate ester such as for example lower alkyl bromide, iodide or chlorides, e.g., ethyl iodide, ethyl chloride, methyl iodide or ethyl bromide, lower alkyl sulfonate, a lower alkyl aromatic sulfonate, e.g., lower alkyl toluene sulfonate or benzene sulfonate; or an ar-lower alkyl halide, e.g., benzyl chloride or phenethyl bromide. The acid addition salts are preferred. These addition compounds are prepared by reacting a base of Formula 1 in an organic solvent with the desired acid or halide usually in excess. The salts generally separate from non-polar organic solvents such as ether readily.

The compounds of this invention are prepared from readily available starting materials as follows:

The ether and thioether starting materials (Formula 2) are sulfonated with chlorosulfonic acid in an inert organic solvent at from about 010 C. to give the novel sulfonyl chlorides of Formula 3. These compounds are then reacted with the desired amine usually in an organic solvent at from about 25-100" C. to form the desired aminoalkoxybenzenesulfonamides. Halogenated preferably chlorinated lower alkylene solvents are preferred such as tetrachloroethylene, chloroform, methylene chloride, etc.

The ethereal starting materials are all well-known compounds or are prepared by procedures identical to those well-known to the art. These synthetic processes together with most of the starting materials used are disclosed in U.S. Pat. No. 2,895,995 and other publications by this group of British workers.

The compounds of this invention are also of interest because of novel steroid blocking activity in plants as Well as in animals. In plant areas this is. manifested by diverse effects on the growing properties of the plant. The compounds, usually as the soluble acid addition salts, are dissolved in water and sprayed onto the plants periodically.

When the compounds of this invention are to be used as pharmacodynamic agents as noted above they are most advantageously combined with a pharmaceutical carrier in dosage unit form and administered internally usually orally in an amount suflicient to obtain the desired therapeutic effects.

The terms lower alkoxy or lower alkyl as used herein denote moieties having a maximum of eight carbons but preferably from 1 to 2 carbon atoms. It will be obvious to one skilled in the art that modifications of the compounds of Formula 1 can be equivalently prepared using known synthetic processes such as other position isomers of the benzenoid substituents, etc. The N-oxide derivatives, e. g., those in Which of Formula 1 is replaced by are prepared by oxidation with hydrogen peroxide and are also potent lipid mobilizing agents. Such modifications are included in this invention.

An alternative method of producing the compounds of this invention is to condense the properly substituted sulfamylphenol,

with a aminoalkyl halide in the presence of an acid binding agent such as an alkali metal hydroxide, carbonate, hydride etc. in a suitable solvent usually at reflux for several hours to prepare compounds of Formula 1. The sulfamylphenols are readily prepared by methods known to the art.

The following examples will fully illustrate the preparation of the compounds of this invention.

Example 1 A mixture of 174 g. (1.5 mole) of chlorosulfonic acid in 250 ml. of dry tetrachloroethane is cooled and maintained at -10 C. while 57.9 g. (0.3 mole) of 2,6-dimethyl-2-(dimethylaminoethoxy)-benzene is added dropwise. The solution is stirred in the cold for /2 hour. The reaction mixture is slowly stirred while 88 g. (1.4 moles) of sodium chloride is added. After warming to room temperature the mixture is heated at reflux for two hours. The mixture is cooled overnight then poured onto 400 g. of ice. The organic layer is separated, washed with 50 ml. of ice Water. Evaporation of a small portion gives the sulfonyl chloride intermediate. The organic layer is then slowly stirred into 300 ml. of cooled 40% aqueous dimethylamine. After stirring at room temperature for 1 /2 hours and on the steam bath for one hour, the organic layer is separated, washed with water and evaporated. The residual base is taken up in ether and acidified with isopropanolic hydrogen chloride. The solid is recrystallized from isopropanol then acetonitrile to give 3,5 dimethyl 4 dimethylarninoethoxy dimethylsulfamyl benzene hydrochloride, M.P. 228230 C.; base, M.P. 73-75 C.

One gram of the base is dissolved in ether and heated at reflux with 750 mg. of methyl iodide to give the methiodide quaternary salt.

Substituting known 2,6-dimethyl-Z-diethylaminoethoxy benzene in the reaction above gives 3,5-dimethyl-4-diethylaminoethoxydimethylsulfamyl benzene plus its sulfonyl chloride intermediate.

Example 2 A mixture of 2.5 g. of 2,6-dichloro-2- diethylaminoethoxy benzene (U.S. Pat. No. 2,895,995), 1 g. of chlorosulfonic acid and chloroform is reacted as in Example 1 to give the sulfonyl chloride. This intermediate (2.75 g.) is dissolved in methylene chloride and reacted with an excess of diethylamine (2 rnl.). After heating at reflux for 4 hours, the mixture is washed with water and evaporated to give 3,5-dichloro-4-diethylaminoethoxy-diethylsulfamyl benzene. The base (500 mg.) is dissolved in ethyl acetate and reacted with an excess of maleic acid to give the maleate salt. Substituting Z-dimethylarninoethoxy-2,6-dichloro benzene and dimethylamine above gives 3,S-dichloro-4-diethylaminoethoxydimethylsulfamyl benzene.

Example 3 A mixture of 1.8g. of dimethylaminoethoxybenzene and 1 g. of chlorosulfonic acid is reacted at 5 C. in chloroform as described. The sulfonation mixture is fractionally crystallized to give 2 and 4-dimethylaminoethoxybenzenesulfonyl chlorides respectively. Q.-dimethylaminoethoxybenzenesulfonyl chloride (500 mg.) is dissolved in methylene chloride and reacted with an excess of alcoholic di methylamine at room temperature then at reflux for 5 hours. Washing and evaporation gives 2-dimethylaminoethoxy-dimethylsulfamylbenzene. Reaction with an excess of sulfuric acid in ether gives the sulfate salt.

Similarly the 4-isomer is reacted with an excess of pyrrolidine to give 4-dimethylaminoethoxy-N-pyrrolidinylsulfonylbenzene.

Example 4 A mixture of 4.1 g. of 2'-dimethylamino-1'-methylethoxy-Z,-dimethylbenzene (U.S. Pat. No. 2,895,995) and 2.5 g. of chlorosulfonic acid in tetrachloroethane is reacted as described to give the sulfonyl chloride intermediate.

This compound (1 g.) in tetrachloroethane is reacted with mg. of morpholine at reflux for 6 hours. Washing and evaporation gives 3,5-dimethyl-4-(2-dimethylamino 1 methylethoxy) -N morpholinylsulfonylbenzene. The base (250 mg.) in benzene is reacted with an excess of ethyl chloride to form the ethochloride quaternary salt.

Substituting ammonia-methanol in a closed container for morpholine gives the sulphonarnide analogue.

Example 5 A mixture of 3.4 g. of 2-iodo-dimethylaminoethoxybenzene hydrochloride (M.P. l46 (3., prepared by reacting 2-iodophenol with dimethylaminoethyl iodide in the presence of base/ethanol) and 1 g. or" chlorosulfonic acid in chloroform is reacted to give the sulfonyl intermediate as in Example 3. This compound (3 g.) is reacted with an excess of isobutylamine to give 3-iodo-4-dimethylaminoethoxy-isobutylsulfamylbenzene as in Example 1. The base (500 mg.) in ether is reacted with dry hydrogen chloride gas to give the hydrochloride.

Replacing the iodo compound by a molar equivalent of 2 trifluoromethyl dimethylaminoethoxybenzene (B.P. l22124 at 22 mm., prepared by refluxing a-trifiuoromethylbromobenzene with sodium dimethylaminoethoxide in excess dimethylaminoethanol for 20 hours) gives the p-sulfonyl chloride. This (2 g.) reacted with alcoholic dimethylamine gives 3-trifluoromethyl-4-dimethylaminoethoxy-dimethylsulfainylbenzene.

Example 6 A mixture of 4.8 g. of 2,6-dimethyl-N-pyrrolidinylpropylthiobenzene (prepared from w-N-pyrrolidinylpropyl chloride and xylenethiol in alcohol with potassium hydroxide at reflux) and 2.1 g. of chlorosulfonic acid in methylene chloride is reacted as in Example 1 to give the crude sulfonyl chloride which is reacted as such with 15 ml. of pyrrolidine at reflux for 4 hours. Working up the reaction mixture as described gives the desired 3,5- dimethyl 4 N pyrrolidinylpropylthio N pyrrolidinylsulfonylbenzene.

Example 7 A mixture of 4.6 g. of 2,6-dimethoxy-diethylamino ethoxybenzene (prepared by condensing the 1,3-dimethylether of pyrogallol and diethylamincethyl bromide) and 2.5 g. of chlorosulfonic acid in tetrachloroethane is reacted as described and the sulfonyl chloride reacted with diethylamine to give 3,5 dirnethoxy-4-diethylaminoethoxydimethylsulfamylbenzene. This base (750 mg.) is shaken with an excess of phosphoric acid in ether to give the phosphate salt. Another portion (500 mg.) is heated at reflux in acetone for 5 hours with methyl benzenesulfonate to give the quaternary salt.

Example 8 A mixture Of 6.2 g. of 2,6-dimethyl-dimethylaminoethylthiobenzene (prepared by reacting at reflux xylenethiol and dimethylaminoethyl bromide in alcoholic potassium hydroxide) and 3.5 g. of chlorosulfonic acid in methylene chloride is reacted by the procedure described above. The resulting sulfonyl chloride (2.3 g.) is reacted with an excess of aqueous dimethylamine as in EX- ample 1 to give 3,5-dimethyl-4-dimethylaminoethylthiodimethylsulfamylbenzene.

Substituting an excess of N-methylpiperazine in chloroform for the dimethylamine gives 3,5 -dimethyl-4-dirnethylaminoethylthio-N-methylpiperazinylsulfonylbenzene.

Example 9 Substituting in equimolar amounts 3,5-dimethyl-diethylaminoethoxybenzene (prepared by reacting 3,5-dirnethylphenol with diethylaminoethyl bromide in alcoholic potassium chloride) for dimethylaminoethoxybenzene in Example 3 gives 2,6-dimethyl-4-diethylaminoethoxy-dimethylsulfarnylbenzene.

Substituting an excess of piperidine in tetrachloroethane for dimethylamine in Example 1 gives 3,5'dimethyl-4- dimethylaminoethoxy-piperidinylsulfonylbenzene.

Substituting 2,6 dimethyl-N-piperidinylbutoxybenzene (prepared by reacting at reflux overnight 2,6-dimethylphenol, w-N-piperidinylbutyl bromide in alcoholic sodium hydroxide) in Example 1 gives 3,5-dimethyl-4-N-piperidinylbutoxy-dimethylsulfamylbenzene.

Substituting 2 chloro-6-methyldimethylaminoethoxy benzene (prepared from the phenol and dimethylaminoethyl bromide) in Example 1 gives 3-chloro-4-dimethylaminoethoxy-S-methyldimethyl sulfamylbenzene.

Example 10 A mixture of 2.5 g. of 3,S-dimethyl-4-dimethylaminoethoxy-dimethylsulfamylbenzene (Example 1) in 17 ml. of 30% hydrogen peroxide solution and 100 ml. of methanol is reacted in the refrigerator for four days. Excess peroxide is destroyed with platinium oxide and the supernatant liquid therefrom evaporated in vacuo to give an oil which solidifies upon trituration under ether; the N- oxide derivative, M.P. 84-855" C.

Example 11 A mixture of 2 g. of 3,5-dimethyl-4-sulfamylphenol, 1 g. of diethylaminoethyl bromide, 1 g. of potassiurn hydroxide and 150 ml. of ethanol is heated at reflux for 10 hours. The mixture is neutralized and evaporated in vacuo. The residue is extracted into methylene chloride. Washing and evaporating the dried organic extract gives 3,5-dimethyl-4-sulfarnyldiethylaminoethoxybenzene.

What is claimed is:

l. A compound selected from the group consisting of a free base, its nontoxic, pharmaceutically acceptable acid addition salts and its nontoxic, pharmaceutically acceptable quaternary ammonium salts formed with medicinally acceptable quaternizing agents selected from the group consisting of halo and sulfonate esters, said free base being of the formula:

Ra s in which:

R and R are members selected from the group consisting of lower alkyl of 18 carbon atoms, and when taken together with the nitrogen atom, piperidinyl, morpholinyl; thiomorpholinyl, pyrrolidinyl and N-lower alkyl piperazinyl.

R and R are respectively members selected from the group consisting of hydrogen, lower alkyl of 18 carbon atoms, and, when taken together with the nitrogen atom, piperidinyl, morpholinyl, thiornorpholinyl, pyrrolidinyl, piperazinyl and N-lower alkyl piperazinyl;

( and R are respectively members selected from the group consisting of lower alkyl, lower alkoxy, triiluoromethyl, hydrogen and halo;

X is a member selected from the group consisting of sulfur and oxygen; and

Alk is a lower alkylene chain of 2-6 carbon atoms.

2. A compound of the formula in which:

R R R R R and R are lower alkyl of 1-2 carbon atoms; and Alk is a lower alkylene chain of 2-6 carbon atoms. 4. A compound of the formula:

5. The nontoxic, pharmaceutically acceptable acid addition salts of 3,5-dimethyl-4-dimethylaminoethoxy-dimethylsulfamylbenzene.

6. 3,5-dimethyl 4 dimethylaminoethoxy-dimethylsulfamylbenzene hydrochloride.

7. A compound of the formula:

OGH

8. A compound of the formula:

OCHa

l OGHa 9. A compound of the formula:

(CH3) 2NS Og S-CHzGHgN (0 H3) 1 10. 3,5-dimethyl 4 dimethylethoxy-dimethylsulfamyl benzene N-oxide.

References Cited in the file of this patent UNITED STATES PATENTS Graf et a1 Sept. 25, 1962 Novello Oct. 23, 1962 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A FREE BASE, ITS NONTOXIC, PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS AND ITS NONTOXIC, PHARMACEUTICALLY ACCEPTABLE QUATERNARY AMMONIUM SALTS FORMED WITH MEDICINALLY ACCEPTABLE QUATERNIZING AGENTS SELECTED FROM THE GROUP CONSISTING OF HALO AND SULFONATE ESTERS, SAID FREE BASE BEING OF THE FORMULA:
 4. A COMPOUND OF THE FORMULA: 